About one-third of the population of the developed world is destined to die from cancer. Current treatment for cancers—including chemotherapy and radiotherapy—are based on killing cancer cells preferentially to normal cells, the so-called “therapeutic window” which accepts significant adverse effects for even marginal slowing of tumor growth. Specific treatments that spare normal cells are urgently needed.
Cancer cells and, indeed, disease cells generally, are different from normal cells in many ways, including a propensity for protein misfolding, intracellularly and at the cell surface. Such misfolded proteins may be the consequence of germ cell or somatic mutation, chromosomal translocation or aneuploidy, mutagenic effects of chemotherapy or radiation therapy, titration of chaperones, molecular crowding in the endoplasmic reticulum and other secretory compartments including the cell surface, aberrant glycosylation and trafficking, impaired clearance and/or degradation, environmental stressors or allosteric influences relevant to the tumor bed (such as lowered pH or increased ligand concentration), and post-translational modifications including oxidation and nitration of select residues. All or some of these factors relevant to cancer contribute to greater dynamic fluctuation and net solvent exposure of specific regions of proteins which are normally rarely accessible in non-cancerous cells. Antibody recognition of these abnormally exposed protein motifs, designated Disease Specific Epitopes (DSE), can serve as a diagnostic cancer marker or cancer treatment target, and provide insight into abnormal cell growth in cancer and other diseases.
Cashman et al have described the principles to be applied when targeting a misfolded protein presented by a disease cell, in WO 2010/04020 published Apr. 15, 2010. This publication describes an algorithm that can be applied to a surface protein of interest, to identify “hot spots” or DSEs that while buried within the protein in its normal conformation are likely to become exposed when the protein misfolds. This approach has been applied successfully to many different targets, by producing antibodies to the predicted DSEs and demonstrating that inhibition of the antibody target yields a desired effect on disease cells. It has been shown, for instance, that cancer cells present misfolded surface proteins that include the prion protein, PrP, (see US 2013-0330275) and that eradication of cancer cells is achieved when those cells are incubated with an antibody that binds to an epitope unique to misfolded PrP (see WO 2013/185215).
The Cashman et al publication also proposes various DSE targets for each of a number of different target proteins commonly associated with disease. These include the protein known as the Fas receptor, or FasR. FasR is a member of the tumour necrosis factor receptor superfamily which is a complex group of cell surface proteins that regulate various cell functions. FasR and its ligand, Fas, are involved particularly in caspase-mediated programmed cell death (apoptosis).
In U.S. Pat. No. 6,846,637, IMED describes specific FAS peptides that are useful to raise therapeutic FAS antibodies. Merck's WO 2004/113387 similarly describes FAS peptides that are produced as Fc fusions and are based on specific FAS domains. Treatment of high grade glioma using FAS antibodies, and of CNS-based inflammatory disorders using any FAS inhibitor, has been proposed by the University of Heidelberg, in their WO 2008/080623 and WO 2010/006772, respectively. Inflammation is treated, according to U.S. Pat. No. 7,510,710, using a combination of FAS antibody and a fatty acid metabolism inhibitor
In U.S. Pat. No. 6,015,559, Immunex describes antibodies that bind FAS extracellular domain (see also U.S. Pat. No. 5,830,469). Sankyo describes a specific FAS antibody that is humanized and designated HFE7 A, whereas Human Genome Sciences describes antibodies that bind to variants of the parental FAS-related TNFR6 protein (see U.S. Pat. No. 7,534,428, U.S. Pat. No. 7,285,267 and U.S. Pat. No. 7,186,800).
The FAS system is a highly intricate signalling complex that requires on-going elucidation of its interactions in order to understand its role(s) in apoptosis and proliferation. To this end, it would be useful to provide reagents that include FAS-binding ligands and antibodies that permit detection and/or inhibition of FAS, particularly in disease states.